By Jeannie Wraight
The Conference on Retroviruses and Opportunistic Infections (CROI) provides an annual snapshot of the year’s most interesting and progressive data on HIV cure and remission research. Here’s a quick run down of some of the highlights presented at this year’s conference.
Kick and Kill
“Kick and kill” is a strategy that proposes to wake up or activate and then eliminate cells that are latently infected with HIV. Active replication allows the immune system to recognize these cells as a danger, making them a target for therapeutic agents. Researchers evaluated in Rhesus monkeys the combination of GS-9620, a TLR antagonist used to activate latent cells, and PGR121, a broadly neutralizing antibody, to kill off the awakened cells. The monkeys had been virally suppressed for two years. ARVs were discontinued before beginning the dual therapy. Viral suppression was maintained for over three months with this combination. At least half the monkeys remained suppressed at six months. In some cases, the virus remerged but the monkeys’ immune systems were able to re-suppress the virus without the need for additional doses. Additionally, researchers found that, even after viral rebound, the virus was at a lower level (viral setpoint) than it had originally been before the monkeys were given the combo, and the monkeys had lower viral DNA levels in their lymph nodes. This study suggests that the duo may have depleted viral reservoirs and allowed for some level of immune control of the virus.
More Validation of U=U
A study relevant to our understanding of viral reservoirs set out to determine if HIV replication occurs in lymph nodes in the presence of viral suppression. Its results are also important to our understanding of the U=U (undetectable equals untransmissable) premise. It has been conclusively established that when a person is undetectable and on sustained treatment for at least six months, he or she can’t transmit HIV to someone else. However, there remains a question as to whether HIV replication occurs elsewhere in the body, such as the lymph nodes, despite it not occurring in the blood, or if ongoing replication in a virally suppressed person stemmed solely from activated latent HIV in viral reservoirs. In this study, Dr. Mary Kearney of NIH’s National Cancer Institute found no evidence of ongoing HIV replication in the lymph node. This study contradicts a previous study published in 2016 that found that HIV replicates in the lymph nodes, helping to replenish viral reservoirs.
CD32+ as a Biomarker?
A major barrier to curing HIV is determining which cells harbor latent HIV. Biomarkers are needed to distinguish latently infected cells from cells not harboring the virus. CD32+ was recently suggested as a biomarker to differentiate the two in CD4 cells. Several studies evaluated this hypothesis and determined CD32+ did not identify latently infected reservoir cells. Studies continue to evaluate other surface markers that can be used as biomarkers, allowing researchers to target these cells.
Early ART in Infants
The “Mississippi baby” first made us aware that very early treatment with ARVs in infants could produce viral suppression for prolonged periods of time. Several studies were conducted to explore the effects of early initiation of ARVs in infants, two of which were reported at CROI 2018. Both studies found that beginning ARVs shortly after birth was safe, feasible and lead to smaller viral reservoirs.
The first study was conducted in Thailand and compared babies aged four to twenty-three weeks who received uninterrupted triple prophylactic ARV therapy since birth and those who did not receive uninterrupted prophylactic ARV therapy. The study also examined virally suppressed babies, with a median age of 2.7 years, who had initiated prophylactic ARV therapy at or after birth. Evaluating markers of HIV persistence, researchers found the infants who received continuous therapy had significantly lower viral loads and lower levels of integrated DNA, than those who didn’t receive continuous therapy. Also lower were the frequency of latently infected cells and the frequencies of cells producing msRNA spontaneously and after stimulation. In the older babies, after ART initiation, those who had started ARVs at birth had significantly lower total and integrated HIV DNA than children starting treatment later and the size of the inducible reservoir correlated with the age at which they began continuous therapy.
In the second study, infants in Botswana were given antiretroviral therapy before the age of seven days old. They were compared to children who started therapy later. Researchers set out to measure immune responses and discover if early treatment limits the size of viral reservoirs and measure immune responses. They found that those treated within seven days had lower viral reservoirs both at the beginning of the study and after eighty-four weeks. Five of the six children who initiated therapy with the first week of life had a negative qualitative HIV DNA PCR and a negative HIV ELISA test after eighty-six weeks.
Originally published in A&U Magazine http://aumag.org/2018/05/21/cure-research-croi-2018/